Spiro-tetraline succinimide compounds



United States Patent Office 3,507,881 SPIRO-TETRALINE SUCCINIMIDE COMPOUNDS Rune Verner Saudberg, Jarua, Sweden, assiguor to Aktiebolaget Astra, Sodertalje, Sweden, a Swedish company No Drawing. Filed Sept. 7, 1966, Ser. No. 577,601 Claims priority, application Sweden, Sept. 17, 1965, 12,164/65 Int. Cl. C07d 27/10 U.S. Cl. 260-3265 12 Claims ABSTRACT OF THE DISCLOSURE Spiro-tetraline succinirnide compounds containing besides the succinimide group, which may be substituted, a bivalent saturated hydrocarbon radical attached to the nitrogen of the amide group, and attached to said hydrocarbon radical any of certain amino groups. The application also discloses the use of such compounds in pharmaceutical preparation, specifically local anesthetics.

The present invention relates to N-alkyl amino-alkyl derivatives of spiro-tetraline succinimides (STS) and their salts and also to a process for their preparation.

More particularly the present invention relates to compounds of the formula:

wherein R is selected from the group consisting of hydrogen halogen, lower alkyl, hydroxy and lower alkoxy; R and R are selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkoxy; R is a bivalent saturated hydrocarbon radical containing at most 6 carbon atoms and Am is an amino group selected from the class consisting of pyrrolidino, piperidino, morpholino and (oH2).,R

wherein R is a hydrogen atom or a lower alkyl group, R is a hydrogen atom, a hydroxy or lower alkoxy group and n is 1-4 in cases when R is a hydrogen atom or 2, 3 or 4 in cases when R is a hydroxy or lower alkoxy group; and a process for their preparation.

An object of the present invention is to discover the formation of alkyl aminoalkyl derivatives of STS and salts thereof. These new derivatives are stable and possess valuable pharmacological properties, especially as local anesthetics.

Another object of the present invention is to provide a method for preparing alkyl aminoalkyl derivatives of STS suitable for manufacturing and for administering to humans and animals.

The preparation of the compounds according to the invention is described by the general reaction:

-OOX

3,507,881 Patented Apr. 21, 1970 wherein R R R and R have the meaning described above and A is an amino group selected from the class consistmg of pyrrolidino, piperidino, morpholino and (OHz)nR wherein R is a hydrogen atom or an alkyl group containing not more than four carbon atoms, R is a hydrogen atom, a hydroxy or alkoxy group containing not more than four carbon atoms, and n is 1-4 in cases where R is a hydrogen atom or 2, 3 or 4 in cases when R is a hydroXy group or alkoxy group containing not more than four carbon atoms, which amino group may be present at the reaction or introduced later in a manner known in the art, and where X, Y and Z are members of the group consisting of hydroxy, alkoxy, halogens, amino, and O tosyl and which are capable of reacting in random manner with each other to form a nitrogen bridge; whereafter A, in cases when A is not equal to Am, is transformed into Am in a manner known in the art. Thus, for instance, X and Y may first react with each other with the formation of an O-bridge (an anhydride is formed) or a -NH-bridge (a cyclic imide is formed). This will be further illustrated by the examples given below.

The preferred method for the preparation of the compounds according to the invention comprises reacting an equivalent amount of a dicarboxylic acid with an alkylene diamine in accordance with the following general scheme:

(III) where R R R R and A have the meaning given above.

Other methods for the preparation of the compounds according to the invention may be represented by the following reaction schemes:

The choice among the different methods of preparation is affected by the structure of the compound to be prepared, i.e. whether a monoor dialkylamino derivative is to be prepared.

The compounds according to the invention may occur in stereoisomeric forms or even in pairs of enantiomorphs. This is due to the presence of one or more asymmetric carbon atoms in the molecule. The present invention comprises the optically pure forms as Well as mixtures of them.

It has now been found that the compounds comprising the present invention possess valuable pharmacological properties, especially as local anesthetics. As such, some of the compounds may be used as topical anesthetics, while others may favorably be used as infiltration anesthetics with an often long-lasting effect.

These advantages are obtained by the use of one or more compounds selected from the group consisting of alkylaminoalkyl derivatives of STS and pharmaceutically acceptable salts thereof. The expression pharmaceutically acceptable salts is recognized in the art to designate an acid addition salt which is physiologically unharmful when administered in a dosage and at an interval (i.e., frequency of administration) that is effective for the indicated therapeutic use of the parent compound.

Typical therapeutically acceptable addition salts of the present invention include, but are not limited to, the salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric or sulphuric acid, organic acids, such as acetic, glycolic, lactic, levulinic, citric, fumaric, maleic, succinic, tartaric, benzoic, and cinnamic acids, as well as sulphonic acids, such as methanesulphonic and sulphamic acid.

In therapy the compounds of the present invention are administered in the form of a solution in a pharmaceutical carrier. The concentration is not important. Widely varyart of local anesthesia, the effectiveness of the anesthesia may be improved by addition of a vasoconstrictor, such as adrenaline, noradrenaline or octapressin.

The amount of local anesthetic which may be used varies widely, and as is well known, depends upon the location and type of anesthesia required. The anesthetic effect, according to the present invention, is induced by applying an amount of a solution of the spiro-tetraline succinimide derivative, which is effective in producing the desired anesthesia.

Repeated applications at therapeutically effective intervals may be made, if desired, to obtain a prolonged anesthetic effect.

The following examples illustrate, but in no way limit, the application of the present invention EXAMPLE 1 Preparation of l-carboxy-l-[1,2,3,4-tetrahydronaphtyl]- acetic acids The preparation of the 1-carboxy-1-[l,2,3,4-tetrahydronaphthyl] acetic acids, which were used as starting materials was made in accordance with the following reaction scheme NC\ /CN NC\ /CN 0 C CH CN u I I ()0 R1 R R. R1 4MB a s V VI VII COzH O 1120 00211 H V H20C NH I Q 1| o I] 0 R1 3 2 R TR R VIII IX The individual steps are described below:

1-Tetrahydronaphthylidenemalononitriles (VI) The Knoevenagel condensation of the tetralones V with malononitrile was effected according to Mowry (J. Am. Chem. Soc. 67, (1945) 1050). In Table 1 the yields, melting points, and analyses of the malononitriles prepared are given.

TABLE 1.1-IETRAHYD RONAPHIHYLINDENEMALONONITRILES (VI) Analyses, percent Calculated Found Yield, R R and R percent M.P C Formula C H N O H N 88-90 CuHuNz 80. 74 5. 81 13. 45 80. 6 5. 82 13. 6 55 110-112 CraHoNzCl 68. 28 3. 97 12. 25 68. 2 4. 00 12. 2 80 117-119 C14H12N2O I. 12. 49 u. 1 5 00 120-121 CI5IIHN2 81. 05 6. 35 12. 61 81. 0 6. 22 12. 7 83 97. 5-99. 5 CuHwNzO 74. 99 5. 38 12. 49 75. 0 5. 57 12. 4 75 77. 5-78 5 C1 I-IuFNz 73. 75 4. 27 13. 20 73. 1 4. 51 13. 2

1 The starting material, 7-fiuorotetralone, was prepared from 7-aminotetralone in a way similar to that usedfor fi-fiuorotetralone by Allmger et al. (J. Org. Chem. 27 (1962, 72). M.P. 62.564 O. Cale. (percent): 0, 73.16; H, 5.52. Found (percent): 0, 73.3; H, 5.43.

1-cyano-1-tetrahydronaphthylmalononitriles (VII) The two solutions obtained by dissolving 0.1 mole of VI in 50 ml. of dry ethanol and 0.2 mole (9.8 g.) of sodium cyanide in 50 ml. of water respectively, were rapidly mixed and the [mixture shaken vigorously. Within a few minutes a homogenous solution was obtained, which was heated on the water bath for four minutes. While stirring and cooling externally 200 ml. of icewater followed by 25 ml. of concentrated hydrochloric acid were added. The precipitated product soon crystalsuch as sodium chloride. Furthermore, as is known in the lizes.

TABLE 2.1-CYANO-1-TETRAHYDRONAPH'IHYLMALONONITRILES VII Analyses, percent Y M Calculated Found 1e R R and R percent M.P.,C. Formula C H N C H N 7-CH H 64 89-91 CH13N 76.57 5.57 17.86 76.3 5.38 18.1 H 99 142-145 CuHinNaCl 65.76 3.94 16.43 65.8 4.07 16.2 H 152-154 C15H1aN30 16.75 16.7 4,4-diCH 99 104-106 C16H15N3 77.08 6.07 16.85 77.0 6.15 17.2 H 93 133-136 CHHIZNZO 71.69 5.21 16.72 71.7 5.25 16.9 H 96 118-121 CuHmFNz 7.1 28 4.21 17.56 70.2 4.21 17.6

l-carboxy-1-tetrahydronaphthylacetic acids (VIII) and spiro succinimides (IX) The nitriles VII were hydrolyzed with decarboxylation by refluxing for 40 hours in a 1:1 mixture of cone. hydrochloric acid and acetic acid (1000 mL/mole). The solvent was evaporated and the residue treated with dilute ammonia. Undissolved imide (IX) was filtered by suction, dried and recrystallized. The alkaline filtrate was acidified, and the precipitated succinic acid derivative (VHI) was filtered 011 and recrystallized from water, occasionally with some formic acid added. The acid and the imide were generally obtained in the ratio 3:1.

The hydrolysis of 7-methoxy-1-cyano 1 tetrahydronaphthylmalononitrile yields only the demethylated acid, 7-hydroxy-l-carboxy-l-tetrahydronaphthyl-acetic acid.

The 7-methoxy acid was prepared by methylating the 7-hydroxy acid with dimethylsulphate in aqueous alkaline solution for 1 hour (reflux). The acid was recrystallized from water.

7-i-propoxy-l-carboxy-l-tetrahydronaphthylacetic acid was prepared from the 7-hydroxy acid (1 mole) by means of sodium ethoxide (3 moles) and isopropylbromide (3 moles) in ethanolic solution. Reaction time (reflux) 8 hours. The acid was recrystallized from water-formic acid.

hydroxide solution. The precipitated base was taken up in ether, dried and converted to its hydrochloride. M.P. 175-7 C. (from dioxane). Yield 62%.

Analysis.-Calcd. (percent): N, 7.68; CI. 9.72. Found (percent): N, 7.7; Cl, 9.70.

EXAMPLE 3 N- a-ethyl-fi-dimethylaminoethyl -STS EXAMPLE 4 N-('y-ethylhydroxyethylaminopropyl)-STS Prepared by replacing the amine in Example 2 with TABLE 3.1CARBOXY-l-TETRAHYDRONAPHTYLAGETIC ACIDS (VIII) Analyses, percent Calcul zted Found Yield, R1 R2 and R3 percent M.P.,C. Formula C H 0 C H 0 H 81 175-7 013111101 66.65 6.02 27.32 66.4 5.99 27.4 70 185-9 011111501 67.73 6.50 25.78 67.3 6.56 25.6 68 193-6 01111110101 58.11 4.88 23.82 58.6 4.88 23.9 .5 163.55.5 014111101 63.62 6.10 30.27 63.3 5.86 30.6 62 151-3 015111101 68.69 6092 24.40 68.4 7.09 24.4 56 195-9 G13H14O5 62.39 5.65 31.97 62.5 5.78 31.7 85 163-5 014E110. 63.62 6.10 30. 27 68.4 5.90 30.3 58 169.5-17L5 011E505 65.74 6.90 27.37 65.6 7.15 27.6 60 1767.5 01511133001 252.2 253 1 Including hydrolyzed imide. 1 Calculated on VI. 8 From 7-methoxy-1-cyauo-1-tetrahdronaphtylmalononitrile. 4 From the phenolic acid. l Equivalent weight.

TABLE 4.Tetrahydronaphthallne-l-splro-tetrallne succlnlmldes (IX) Analyses, percent Calculated Found R1 R2 and R3 M.P., 0. Formula C H N C H N H 155-7 C11H13N01 72.54 6.09 6.51 72.5 5. 9a 6.52 7-0H5 H 142-4 CuHlsNOz 73.34 6.59 6.11 73.4 6.50 6.08 7-c1 H 218-20 CiaHuNOzGl 62.53 4. 85 5.61 62.2 4.80 5.53 ammo".-. H 163.5-5 CnHuNO; 68.55 6.16 5.71 68.4 6.11 5.67 H 4,4-dlCH1 174.5-7 CUHHNOZ 74.05 7.04 5.76 73.6 6.86 5.82

3-ethylhydroxyethylaminopropylamine and distilling the EQMPLE 2 product, B.P. 185 c./0.00s mm. Hg. N-(.y.diethylaminopropyl)-STS Analysm-Calcd. (percent): N, 8.13; O, 13.9. Found (percent): N, 8.24; O, 14.1. drid om und Equlmolecular amounts oflthe :nhy3 e of c po EXAMPLE 5 VIII prepared from VIII (R =R =R =H) by refluxmg for 1 hour in tetrachloroethane under a water separator, -(Y- y y y p py M- 6 and dlethylammopl'opylamlne F Prepared by replacing the amine in Example 4 with mlxed and heated for 1 hour at 160 C. After cooling, -m thylmethoxyethylaminopropylamine. B.P. C./ the product was dissolved in dilute hydrochloric acid. 0.005 mm. Hg. The solution was washed with ether and then the solu- 75 Analysis.Calcd.: N, 8.13%; eq. w., 344.5. Found:

tion was made alkaline by the addition of dilute sodium N, 7.9%; eq. w., 344.

7 EXAMPLE 6 N-(e-dimethylaminobutyl)-4,4-dimethyl-STS Prepared from 1-carboxy-4,4-dirnethyl-tetrahydronaphthylacetic acid and 4-dimethylaminobutylamine in the r same way as in Examples 2 and 3. Yield 59% of hydrochloride With M.P. 180.53.5 C.

Analysis.Calcd. (percent): N, 7.39; CI, 9.36. Found (percent): N, 7.4; C1, 9.4.

EXAMPLE 7 N-(v-diethylaminopropyl)-7-methyl-STS Prepared from 1-carboxy-7-methyl-tetrahydronaphthylacetic acid and 3-methylethylaminopropylamine yield 60% with B.P. l75-80 C./0.05 mm. Hg.

Analysis.-Calcd.: N, 8.18%; eq. w., 342.5. Found: N, 8.2%; eq. w., 343.

EXAMPLE 8 N- ('y-dimethylaminopropyl -6-methoxy-STS Prepared from 1-carboxy-6-methoxy-tetrahydronaphthylacetic acid and 3-dimethylaminopropylamine by heating at 180 C. for 2 hours. Hydrochloride M.P. 158- 60 C.

Analysis.Calcd. (percent): N, 7.63; CI, 9.66. Found (percent): N, 7.5; CI. 9.4.

EXAMPLE 9 N-(B-methylaminoethyl)-7-C1-STS Prepared from l-carboxy-7-chloro-tetrahydronaphthylacetic acid and methyl-aminoethylarnine by heating at 180 C. for 1 hour. Hydrochloride M.P. 261-4 C.

Analysis.-Calcd. (percent): N, 8.16; CI, 20.66. Found (percent): N, 7.8; Cl, 20.9.

EXAMPLE 10 N-(y-diethylaminopropyl)-7-hydr0xy-STS Prepared from 1-carboxy-7-hydroxy-l-tetrahydronaphthylacetic acid and 3 diethylaminopropylamine by heating at 180 C. for 2 hours. Hydrochloride M.P. 190-192.5 C.

Analysis.Calcd. (percent): N, 7.09; Cl, 8.98. Found (percent): N, 7.03; Cl, 8.94.

EXAMPLES 13-54 AND 73 The compounds of Formula I in Table 5 (in which R, R R R and Am have the specified significance) were obtained in a manner analogous to that described in Examples 6-12.

TABLE 5.-SPIROTETRALINE SUCCINIMIDES (I) Analyses, percent Calculated Found 13 H .H -CHzCHz N(CH@)2- 1968 C 8.68 10.98 3.7 10.9

14 H H CH3 N(CH9)2 204-6" C 8. 32 10. 53 8.4 10.6

-CII2 '(I)H- 15 H H CH; -N(CH1)1 246-9 0. (d) 8.32 10.52 8.3 10.6

( HCH2' 16 H H C2115 -N(CH3): 7. 9s 10. 11 7.8 10.0

OHz-CH 17 H H I 250- C 8. 03 10. 16 7. 9 10. 3

NCHa 1s H H CH2CH2- 7.5 0. (base) 8.58 328.4 8.6 1326 19A H H CH3 N(C2H5)2 17780 C 7.68 9. 72 7.6 9. 7

GHz( JH 19B H H CH3 -N(C2H5)2 2235.5 C 7. 68 9. 72 7. s 9. s

-CHz-( JH 20 H H CH; -N(C2H5)2 -6 C 7. 68 9. 72 7. 7 9. 6

(|3HCH2- 21A H H CzHu N(C2H5)2 200'3 C 7. 39 9. 37 7. 3 9. 4

CHzCH- 21B H H C2111 --N( 2 s)2 161.5-5 O 7.39 9. 37 7. 3 9.4

CH2-CH- 22 H H C2H5 N(C2H5)z 1645 0 7.39 9. 37 7.3 9. 5

OH-OHz 23 H H CH2GH2CH (CHz)2 144-6 0 8.32 10.53 8.1 10.5

24A H H CH3 -N(CHa)2 191-13 0 7.98 10.11 7.8 9.8

1 1 EXAMPLE 55 N- (,B-methylhydroxyethylaminoethyl) -STS 1.0 g. (50% excess) of freshly distilled ethylene oxide in 25 ml. of methanol was added dropwise to 4.2 g. of the compound prepared according to Example 36, dissolved in 30 ml. of methanol. The mixture was left at room temperature for half an hour and then heated at 40 C. for 2 hours. The solvent was evaporated and the residue worked up as described in Example 2, except for the fact that the crude base was not converted into hydrochloride but was distilled. Yield 3.5 g., boiling at 180- 190 C./0.03 mm. Hg.

- Analysis.Calcd. (percent): N, 8.86; O, 15.2. Found (percent): N, 9.01; O, 15.2.

EXAMPLE 56 N- 6-methylhydroxyethylaminobutyl) -STS In a manner analogous to Example 55 N-(6methylhydroxyethylaminobutyl)-STS was prepared from ethylene oxide and the compound prepared according to Example 38. Boiling at 180l90 C./0.01 mm. Hg.

Analysis.--Calcd. (percent): N, 8.13%; eq. w., 344.5. Found (percent): N, 8.26%; eq. w., 349.6.

EXAMPLE 57 N('y-diethylaminopropyl) -STS Equimolecular amounts of 1,2,3,4-tetrahydronaphthalin-l-spiro-3'-2'-5'-pyrrolidindion (IX, R =R =R =H) and diethylaminopropylamine were heated together at 200 C. for 8 hours. The resulting mixture was worked up as described in Example 2. Yielding 21% of product, M.P. 175-7 C. identical with the compound obtained in Example 2.

EXAMPLE 58 N-(B-diethylaminoethyl) -STS To a solution of 0.46 g. (0.02 mole) of sodium in 40 ml. of methanol were added 2.14 g. (0.01 mole) of IX (R :R =R =H), followed by a solution of 1.97 g. (0.01 mole) of B-diethylaminoethylbromide hydrobromide in 15 ml. of methanol. After refluxing for 9 hours the solvent was evaporated and the residue worked up as before. Yield of hydrochloride 1.7 g. (49%) M.P. 193-5 C.

Analysis.-Calcd. (percent): N, 7.98; CI, 10.11. Found (percent): N, 8.0; Cl. 10.0%

EXAMPLE 59 N- (B-diethylaminoethyl) -STS A mixture of 10 ml. of diethylaminoethylalcohol and 2.14 g. of the compound corresponding to Formula IX (R =R =R =H) were slowly heated to 180 C. and kept at this temperature for 4 hours. After heating at 220 C. for another 2 hours the product was distilled. The fraction boiling about 160 C. at 0.2 mm. Hg. was converted to hydrochloride and recrystallized from ethylacetate-methanol. Yield 1.1 g. with M.P. 192.5 C., not depressed in admixture with the compound prepared in Example 58.

EXAMPLE 60 N-(iB-aminoethyl) -STS To 20 ml. of ethylendiamine were added in small portions 4.3 g. of the anhydride of VIII (R =R =R =H). The mixture was then refluxed for 2 hours. Excess ethylenediamine was distilled at mm. Hg. and the residue fractionated at 0.2 mm. Hg. 3 g. of the product were obtained in the range l50l70 C. This was converted to hydrochloride. Yield 1.4 g. M.P. 2435 C. (from methanol-ethylacetate) Analysis.-Calcd. (percent): N, 9.51; Cl, 12.03. Found (percent): N, 9.4; Cl, 11.9.

1'2 EXAMPLE 61 N- (,B-n-butylaminoethyl -STS To a cold solution of 3.9 g. of the amine, obtained according to Example 60, in 75 ml. of ethanol, 1.3 g. of butyraldehyde were continuously added. The mixture was hydrogenated over 0.5 g. of Pt. in a Parr apparatus (4 kg./cm. The product was isolated as hydrochloride. Yield 2.7 g., M.P. 15860.5 C. (from ethylacetate-methanol).

Analysis.Calcd. (percent): N, 7.98; Cl, 10.11. Found (percent): N, 7.9; Cl, 10.1.

EXAMPLE 62 N-('y-methyl-v-diethylaminopropyl)-STS (A) A solution of 1.4 g. (0.01 mole) of ,B-diethylaminobutyronitrile and 4.3 g. (0.02 mole) of the anhydride of the compound corresponding to Formula VIII (R =R =R =H) in 50 ml. of dioxane was hydrogenated over 0.5 g. of platinaoxide in a Parr apparatus at 60 C. for 12 hours. The reaction mixture Was filtered and the solvent evaporated at C. for 1 hour. The residue was worked up as usual. The crude hydrochloride was recrystallized repeatedly from ethylacetate -methanol yielding 0.55 g. of product M.P. 230-3 C.

Analysis.Calcd. (percent): N, 7.39; Cl, 9.37. Found (percent): N, 7.3; Cl, 9.3.

(B) The mother liquor from the first recrystallization was evaporated to half its volume and the hydrochloride obtained recrystallized from the same solvent yielding 0.6 g. of product M.P. l848 C.

Analysis.Calcd. (percent): N, 7.39; Cl, 9.37. Found (percent): N, 7.3; CI, 9.3.

EXAMPLE 63 N-(B-n-butylamino-ethyl) -STS (A) To a solution of 0.23 g. of sodium in 20 ml. of ethanol 2.14 g. of the imide corresponding to Formula IX (R =R =R =H) were added, followed by 10 ml. of 1,2-dibromethane. The mixture was refluxed overnight, filtered, the solvent evaporated and the residue distilled, yielding 2.5 g. of product b 150 C.

(B) 2 g. of the bromo-compound thus obtained, were refluxed overnight with an equal amount of n-butylamine in 10 m1. of toluene. The product was isolated as hydrochloride. Yield 0.6 g., M.P. 1569 C. (from ethylacetatemethanol), not depressed in admixture with the compound prepared according to Example 61.

EXAMPLE 64 (A) N-(v-hydroxypropyD-STS 12.9 g. of the anhydride of the compound corresponding to Formula VIII (R =R =R =H) and 25 ml. of 3- aminopropanol were heated at 200 C. for 2 hours. The product was fractionally distilled, yielding 12.2 g. b C.

Analysis.Calcd. (percent): N, 5.17. Found (percent): N, 5.3.

(B) N- ('y-tosyloxypropyl) -STS The above alcohol (12.1 g.) was tosylated in the usual manner, yielding 10.6 g. of product M.P. 1068 C. (from ethanol).

Analysis.-Calcd. (percent): N, 3.28; S, 7.50. Found (percent): N, 3.3; S, 7.3.

(C) N- -pyrrolinopropyl) -STS A mixture of 4.25 g. (0.01 mole) of the tosyl compound and 1.5 g. (0.02 mole) of pyrroline in 35 ml. of toluene, was stirred at 45 C. for 2 hours and refluxed for another 2 hours. The precipitated salt Was filtered and the filtrate washed with water and then extracted with dilute hydrochloric acid. The acid extracts were made alkaline and the precipitated base taken up in ether. After EXAMPLE 65 TABLE 6.LOCAL ANAESTHETIC ACTIVITY OF SPIRO- TETRALINE SUCOINIMIDES Compound Isolated frog Toxicity i.v., according to sciatic nerve LDso mgJkg. Example N 0. Rabbit cornea 1 block 1 white mouse 2-51.. 1. 2 1.0 21 1. 5 0. 6 35 1. 5 0. 3 32 1. 6 0. 8 24 4. 0. 6 18 0. 8 0. 68 0. 8 0. 4 29 1. 7 1 16 2. 6 0. 9 22 2. 5 0. 8 24 0. 7 0. 3 38 1. 2 1. 0 23 0. 9 1. 0 24 0. 5 0. 5 15 0. 6 0. 1 68 l. 6 1. 0 15 1. 7 0. 8 17 2. 9 0. 6 21 1. 0 0. 8 22 1. 0 1. 0 19 1. 7 1. 0 23 1. 0 0. 4 31 2. 5 0. 6 25 1. 7 1. 0 17 1. 7 0. 8 27 1. 9 0. 8 23 1. 0 0. 9 19 0.7 0. 3 39 O. 9 0. 5 27 1. 4 0. 5 21 1. 5 0. 6 24 1. 3 1. 0 19 1. 3 0. 5 32 l. 4 0. 6 24 0. 2 0. 1 59 1. 2 0. 5 24 0 0. 4 55 2 0. 6 26 0. 8 0. 2 37 4. 4 0. 3 15 0. 5 0. 5 50 0. 9 0. 6 41 0. 9 0. 4 26 3. 8 0. 4 23 0. 8 0. 5 32 1. 3 0. 7 35 0. 9 0. 3 32 1 0. 7 30 1. 7 0. 7 20 1 0. 4 29 4 0. 6 14 0. 5 1 28 3. 3 21 17 4 21 13 0. 7 0. 9 51 1. 4 1 40 0. 7 0. 4 22 0. 6 24 2. 9 1. 0 5. 7 1. 0 7. 4 1. 7 0. 9 20 7. 4 1 13 1 Wiedling, 8., Acta Pharmacol. et Toxicol. 8 (1952), 117.

2 Manro, A., Truant, A.P., an

McCawley, E.L., Yale J. Biol. Med. 21 (1948), 113.

7 Some examples are denoted A and B. This refers to those cases when the two epimers in a mixture have been separated as described in Examples 3 and 63.

' The enantiomers of the racemic imides can be separated in two ways, either by direct resolution by means of an optically active acid such as tartaric acid, dibenzoyltartaric acid, camphorsulphonic acid etc., or by first resolving the succinic acid, which is then coupled with the appropriate amine. The latter method is illustrated for the preparation of the antipodes of the compound, the racemic modification of which is described in Example 2.

EXAMPLE 66 Resolution of l-carboxy-l-[l,2,3,4-tetrahydronaphthyl] acetic acid (A) To a hot solution of 207.1 g. of the acid in 2200 ml. of 90% alcohol were added 260.5 g. of cinchonidine. The solution was filtered and then 1750 ml. of water were added. The solution was left to cool down to room temperature and then placed in a refrigerator for twenty-four hours. 385 g. of salt were obtained which was recrystallized twice from alcohol (4 resp. 2 1.). The acid was liberated from the remaining salt (142.5 g.) and recrystallized from water-formic acid, yielding 56.5 g.

Enantiomers of N- ('y-diethylaminopropyl)-STS Equimolecular amounts of or ()-1-carboxy-1- [1,2,3,4 tetrahydronaphthyl] acetic acid and -diethylaminopropylamine were heated together at 180 C. for 2 hours. The reaction mixture was Worked up as described in Example 2. The hydrochloride was recrystallized twice from ethyl acetatemethanol, yield about 60%, Ml. 172- 4 C., [a] =i2.55.

EXAMPLE 68 The local anaesthetic activity of the enantiomers of N- -diethylamino-propyl) -STS The activity was examined by the methods given in Example 65.

TABLE 7 Isolated frog Toxicity i.v., sciatic nerve LDS rug/kg. Compound Rabbit cornea block white mouse EXAMPLE 69 Injectible solution containing N-(y-diethylaminopropyl)-STS To ml. of hot, sterilized Water 0.1 g. of methyl phydroxybenzoate were added while stirring and heating. After all of the benzoate was dissolved 2 g. of N-(v-diethylaminopropyl)-STS hydrochloride and 0.6 g. of sodium chloride were added while stirring. The pH adjusted to 7 by adding sodium hydroxide. Sterilized water Was added to 100 ml.

EXAMPLE 7O Injectible solution containing N-(y-diethylaminopropyD- STS and vasoconstrictor To 100 ml. of hot, sterilized water 0.1 g. of methyl p-hydroxybenzoate', 2 g. of N-('y-diethylaminopropyD- STS hydrochloride and 0.6 g. of sodium chloride were added in the same manner as described in Example 69, but the solution was protected from atmospheric oxygen by working in a, nitrogen atmosphere. 0.05 g. of sodium pyrosulfite were then dissolved, whereafter 1 mg. of adrenaline was added. The pH was adjusted to 4 by adding sodium hydroxide. Sterilized water was added to 100 ml.

EXAMPLE 71 Pharmaceutical jelly containing N-(y-diethylaminopropyl)-STS To 80 ml. of distilled water 0.5 g. of N-(y-diethylamin0propyl)-STS hydrochloride was added. To this solution 4 g. of methylcellulose were added while stirring, and when all methylcellulose was dissolved a solution of 50 mg. of chlorhexidine diglyconate in 10 ml. of water was added and the volume was adjusted to 100 ml. by addition of distilled water.

EXAMPLE 72 Pharmaceutical ointment containing N-(y-diethylaminopropyl) -STS Equal amounts (27 g. of each) of polyethyleneglycol 300 and polyethyleneglycol 1540* were melted together with 19 g. of polyethyleneglycol 3000 at 60 C. Then 25 g. of propyleneglycol and finally 2 g. of N-(y-diethylaminopropyD-STS were added and the ointment was homogenized.

EXAMPLE 73 N- -diethylaminopropyl -7 fiuoro-STS See above on page 20.

In the specification and the claims the expression lower alkyl and lower alkoxy groups refer to groups containing not more than four carbon atoms.

I claim:

1. A compound of the formula:

N.R .Am

wherein R is selected from the class consisting of a hydrogen atom and a lower alkyl group containing not more than four carbon atoms; R is selected from the group consisting of a hydrogen atom, a hydroxy and a lower alkoxy group consisting of not more than four carbon atoms; and n is 14 in cases where R is a hydrogen atom and is 24 in cases where R is from the class consisting of a hyd-roxy and lower alkoxy group containing not more than four carbon atoms.

2. A compound according to claim 1 and their pharmaceutically acceptable acid addition salts, wherein R R and R are hydrogen.

3. A compound according to claim 1 and their pharmaceutically acceptable acid additionsalts, wherein R is a methoxy group.

4. N (,8 methylhydroxyethylaminoethyD-spiro-tetralinesuccinimide and its pharmaceutically acceptable acid addition salts.

5. N (6 methylhydroxyethylaminobutyl)-spiro-tetralinesuccinimide and its pharmeutically acceptable acid addition salts.

6. N ('y diethylaminopropyl)-7-hydroxy-spiro-tetralinesuccinimide and its pharmaceutically acceptable acid addition salts.

7. N (6 diethylaminobutyl) 7-methoxy-spiro-tetralinesuccinimide and its pharmaceutically acceptable acid addition salts.

8. N ('y dimethylaminopropyl 6-methoxy-spiro-tetralinesuccinimide and its pharmaceutically acceptable acid addition salts.

9. N ('y diethylaminopropyl)-6-methoxy-spiro-tetralinesuccinimide and its pharmaceutically acceptable acid addition salts.

10. N (v diethylaminopropyl)-spiro-tetraline succinimide and its pharmaceutically acceptable acid addition salts.

11. N ([3 methyl-B-diethylaminoethyl)-spiro-tetraline suecinimide and its pharmaceutically acceptable acid addition salts.

12. N (6 diethylaminobutyl)-spiro-tetraline succinimide and its pharmaceutically acceptable salts.

References Cited UNITED STATES PATENTS 3,210,374 lO/l965 Huebner 260 --326.5 3,224,936 12/1965 Prill et a1. 26O 326 .5 XR 3,256,277 6/1966 Rice 260247.1 3,257,398 6/19'66 Grogan et al 260'247.5

ALEX MAZEL, Primary Examiner J. A. NARCAVAGE, Assistant Examiner US. Cl. X.R.

2 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,507,881 Dated April 2l l970 Inventor(s) Rune Verner Sandberg It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

[ "I Col. l, Table 1, last line, 6th column, "73.75" should be 73-57 "3 Col. 5, Table 2, last line, 6th column, "7 28" should be 70. 28 Col. 5, Table 3, 5th line of column 7, 6092" should be 6.92

Col. 13, line 1, "hydor'chlor'ide" should be hydrochloride Col. 13, line 58, "63" should be 62 Col. l l, line 48, after "pH" insert was Col. 16, line 3 after "acceptable" insert acid addition Column 8, line 13, "N-( -diethylaminobuty1)-7- methoxy-STS" should read N- (6-diethylaminobutyl) -7- methoxy-STS ennui?) AND SEZLED JAE-I 1971 (SEAL) Atteat:

m MJletclm-J mull. Wm It. dbmillioner o1 Petsuts 

